Kombiglyze XR
Kombiglyze XR
Generic Name
Kombiglyze XR
Drug Class
Use the fixed‑dose combo to improve patient adherence, but always individualize dosing based on renal function and monitor for lactic acidosis—this combination can be life‑changing when correctly applied.
Mechanism
- Sitagliptin: Inhibits dipeptidyl‑peptidase‑4 (DPP‑4), prolonging the activity of incretin hormones (GLP‑1 and GIP). Incretin stimulation ↑β‑cell insulin secretion, ↓α‑cell glucagon release, and improves glycemic control independently of insulin sensitivity.
- Metformin (extended‑release): Decreases hepatic gluconeogenesis, increases peripheral insulin‑mediated glucose uptake, and improves insulin sensitivity. The extended release allows once‑daily dosing and reduces peak plasma metformin concentrations, mitigating gastrointestinal intolerance.
The combination provides complementary, additive glucose‑lowering effects without overlapping toxicity profiles.
Pharmacokinetics
| Parameter | Metformin (XR) | Sitagliptin |
| Absorption | Rapidly absorbed; peak time ~3 h; XR formulation prolongs Tmax to ~6–8 h | Rapid; Tmax ~3 h |
| Bioavailability | ~50 % (with food) | ~45 % |
| Distribution | Large volume (Vd ≈ 8 L/kg) | Vd ≈ 2.5 L/kg |
| Protein binding | <2 % | 16 % |
| Metabolism | None significant | Primarily hydrolysis; ~90 % unchanged |
| Excretion | Renal (kidney) unchanged; CLr 0.61 L/h/kg | Renal; CLr 5.8 L/h (≈ 50 % renal) |
| Half‑life | ~10 h (XR) | ~12 h |
| Onset of action | 30–60 min | 1–4 h |
| Food effect | Enhances bioavailability; XR mitigates peak‑related GI side‑effects | Minor |
Renal impairment markedly prolongs sitagliptin’s half‑life and increases exposure; metformin is partially cleared renally, so combined exposure can rise in CKD. Dose adjustments are recommended.
Indications
- Adult patients with type 2 diabetes mellitus requiring dual‑mechanistic glucose control.
- Adjunct to diet, exercise, and/or another antidiabetic agent (e.g., insulin, sulfonylureas, GLP‑1RA) when monotherapy does not achieve target HbA1c of 7 %.
- Especially useful in patients needing once‑daily dosing and a fixed‑dose combination.
Contraindications
Contraindications
• Type 1 diabetes mellitus or diabetic ketosis.
• Severe renal impairment (CKD stage 4 or eGFR < 30 mL/min/1.73 m²).
• Severe hepatic disease or liver failure.
• Metabolic acidosis (incl. ketoacidosis, lactic acidosis).
Warnings
• Lactic acidosis: Rare but potentially fatal; monitor renal, hepatic function and risk factors (COPD, heart failure).
• Hypoglycemia: Low risk as monotherapy; higher risk when combined with sulfonylureas or insulin.
• Gastrointestinal intolerance: Nausea, diarrhea, abdominal discomfort—mitigated by XR formulation.
• Pregnancy & lactation: Category B; limited data, consider risk–benefit.
• Drug interactions: CYP3A4 inhibitors/inducers have minor effect; potent inhibitors (e.g., quinidine) ↑ sitagliptin levels; strong renal competitors (metformin) increase risk of lactic acidosis.
Dosing
1. Initial dose: One tablet (100 mg metformin XR + 50 mg sitagliptin) once daily, taken with a meal (preferably the biggest meal of the day).
2. Titration: Increase to 200 mg/100 mg daily (two tablets) after 4 weeks if glycemic targets not met.
3. Max daily: 250 mg metformin XR + 200 mg sitagliptin (three tablets) – never exceed 4000 mg metformin or 200 mg sitagliptin per day.
4. Renal adjustment:
• eGFR 30–50 mL/min/1.73 m²: Reduce to 100 mg/50 mg (one tablet) daily.
• eGFR <30 mL/min/1.73 m²: Consider alternative therapy; not recommended.
5. Switching: If switching from immediate‑release metformin, add an initial 6–8 h delay before first XR dose to avoid overlap.
Administration tips
• Avoid abrupt discontinuation of metformin in patients with ICD‑diagnosed heart failure; mitigate lactic acidosis risk.
• High‑fat or high‑protein meals may prolong absorption slightly—generally not clinically significant.
Adverse Effects
| Category | Events (Common) | Serious / Rare |
| Gastrointestinal | Nausea, diarrhea, vomiting, abdominal pain (≈10–15 %) | Severe diarrhea; electrolyte imbalance |
| Lactic acidosis | Rare (<1/100 000) | Fatal |
| Hypoglycemia | Rare (<1 %) | Severe when combined with insulin or sulfonylureas |
| Allergic reactions | Rash, pruritus | Anaphylaxis |
| Renal | Elevated serum creatinine (monitor) | Acute kidney injury (rare) |
| Metabolic | Hyperuricemia | Gout flare (rare) |
Note: The XR design reduces peak metformin concentration, thereby decreasing GI upset versus immediate‑release formulations.
Monitoring
| Parameter | Frequency | Rationale |
| HbA1c | Every 3 months (or earlier if dose changed) | Assess glycemic control |
| Serum creatinine/eGFR | Before initiation and every 3 months | Dosing adjustment, safety |
| Liver function tests | Baseline, then every 6 months | Detect hepatic dysfunction |
| Weight & BMI | At each visit | Metformin promotes modest weight loss |
| Signs of lactic acidosis | Clinical surveillance | Nausea, malaise, tachypnea, abdominal pain |
Hypoglycemia symptoms | Patient education | Prompt recognition |
| Foot examination (if indicated) | As per diabetes guidelines | Detect neuropathy or ulcer risk |
Clinical Pearls
- Once‑daily adherence dramatically improves persistence compared to multiple once‑daily monotherapies; ideal for patients with pill burden issues.
- XR formula mitigates the peak‑related GI side‑effects common with immediate‑release metformin; still, starting at 100 mg helps especially in previously intolerant patients.
- Renal monitoring is essential; a 30 % dose reduction in eGFR 30–50 mL/min/1.73 m² maintains therapeutic levels while minimizing lactic acidosis risk.
- Combination therapy with GLP‑1RAs or insulin can enhance efficacy but heightens hypoglycemia risk; keep routine glucose monitoring in place.
- Pregnancy: Metformin is category B; however, sitagliptin data are limited—consider risk benefit if glycemic control is poor.
- Drug interactions: caffeine and alcohol may increase metformin absorption; advise moderated intake.
- Transition from immediate‑release: If a patient is on 1000 mg metformin IR, you can switch directly to 100/1000 mg XR daily. Provide a 4–6 h window before first XR dose to avoid overlap.
- Missed dose: If a single dose is missed, take it when remembered; avoid doubling the next dose.
--
• Quick Reference Table
| Aspect | Key Point |
| Drug class | DPP‑4 inhibitor + extended‑release biguanide |
| Typical daily dose | 100 mg metformin XR + 50 mg sitagliptin |
| Renal cut‑off | eGFR <30 mL/min/1.73 m² – discontinue |
| Maximum | 250 mg metformin XR + 200 mg sitagliptin |
| Monitoring | HbA1c, eGFR, lactic acidosis signs |
| Major risk | Lactic acidosis in renal/hepatic compromise |
| Adverse effect | GI upset (XR reduces incidence) |
Final Tip: Use the fixed‑dose combo to improve patient adherence, but always individualize dosing based on renal function and monitor for lactic acidosis—this combination can be life‑changing when correctly applied.